Reconfigurable Hardened Latch and Flip-Flop for FPGAs

In this paper, we propose Joint Latch (JLatch) and Joint Flip-Flop (JFF), two novel reconfigurable structures which bring the reconfigurability of reliability to user latches and flip-flops (FFs) in reconfigurable devices such as FPGAs. Specifically, we implement two reconfigurable storage elements that exploit a trade-off between reliability and amount of available resources. In fault prone conditions, JLatch (or JFF) is configured in such a way that four pre-selected normal static latches (or FFs) are combined together at circuit level to form one hardened storage cell. Solution focuses on transient faults such as soft errors, where we show that critical charge is increased by at least three orders of magnitude (1000X) to practically bring immunity against any Single Event Upset (SEU). If four latches inside an FPGA logic block are far enough, it can effectively cope with Multiple Bit Upsets (MBUs) as well. Additionally, provided that special transistor sizing is applied (only necessary for some latch structures), JLatch and JFF take advantage of a novel self-correcting technique to correct any single fault immediately. Our solution provides reconfigurability of reliability with negligible performance and area overhead with only one (two) extra transistor(s) per latch (FF). The delay of this technique is less than the delay of conventional TMR (Triple Modular Redundancy) technique with a majority voter at output. © 2017 IEEE

NS-SRAM: Neighborhood Solidarity SRAM for Reliability Enhancement of SRAM Memories

Technology shift and voltage scaling increased the susceptibility of Static Random Access Memories (SRAMs) to errors dramatically. In this paper, we present NS-SRAM, for Neighborhood Solidarity SRAM, a new technique to enhance error resilience of SRAMs by exploiting the adjacent memory bit data. Bit cells of a memory line are paired together in circuit level to mutually increase the static noise margin and critical charge of a cell. Unlike existing techniques, NS-SRAM aims to enhance both Bit Error Rate (BER) and Soft Error rate (SER) at the same time. Due to auto-adaptive joiners, each of the adjacent cells' nodes is connected to its counterpart in the neighbor bit. NS-SRAM enhances read-stability by increasing critical Read Static Noise Margin (RSNM), thereby decreasing faults when circuit operates under voltage scaling. It also increases hold-stability and critical charge to mitigate soft-errors. By the proposed technique, reliability of SRAM based structures such as cache memories and register files can drastically be improved with comparable area overhead to existing hardening techniques. Moreover it does not require any extra-memory, does not impact the memory effective size, and has no negative impact on performance. © 2016 IEEE

Register file reliability enhancement through adjacent narrow-width exploitation

Due to the increasing vulnerability of CMOS circuits, new generations of microprocessors require an inevitable focus on reliability issues. As the Register File (RF) constitutes a critical element within the processor pipeline, it is mandatory to enhance the RF reliability to develop fault tolerant architectures. This paper proposes Adjacent Register Hardened RF (ARH), a new RF architecture that exploits the adjacent byte-level narrow-width values for hardening registers at runtime. Registers are paired together by some special switches referred to as joiners. Dummy sign bits of each register are used to keep redundant data of its counterpart register. We use 7T/14T SRAM cell [6] to combine redundant bits together to make a single bit cell which is, by far, more resilient against faults. Our simulations show that with 3% to 12% power overhead and 10% to 20% increase in area, in comparison to baseline RF, we can obtain up to 80% reduction in soft error rate (SER). © 2016 IEEE

The impact of meridian balance method electro-acupuncture treatment on chronic pelvic pain in women: a three-armed randomised controlled feasibility study using a mixed methods approach

Introduction:\ud Chronic pelvic pain (CPP) is estimated to affect 6%–27% of women worldwide. In the United Kingdom, over 1 million women suffer from CPP and it has been highlighted as a key area of unmet need. Standard treatments are associated with unacceptable side effects. The meridian balance method electro-acupuncture (BMEA), and traditional Chinese medicine health consultation (TCM HC) (BMEA + TCM HC = BMEA treatment) may be an effective adjunct to standard treatment.\ud \ud Aim:\ud The aim of our study was to evaluate the feasibility of a future trial, to determine the effectiveness of the BMEA treatment for CPP in women. The primary objectives were to determine recruitment and retention rates. The secondary objectives were to assess the effectiveness of the BMEA treatment and acceptability of the study’s methodology.\ud \ud Methods:\ud Women with CPP were randomised into BMEA treatment (group 1), TCM HC alone (group 2) (each intervention administered twice weekly for 4 weeks) or National Health Service standard care (NHS SC, group 3). Primary outcomes were assessed by the proportion of eligible participants randomised, and the proportion of randomised participants who returned follow-up questionnaires. Interventions were assessed by validated pain/physical/emotional functioning questionnaires at baseline (0), 4, 8 and 12 weeks. Focus groups and semi-structured telephone interviews were embedded in the study.\ud \ud Results:\ud A total of 30 women (51% of those referred) were randomised over 8 months. Retention rates were 80% (95% confidence interval (CI): 74–96), 53% (95% CI: 36–70) and 87% (95% CI: 63–90), in groups 1, 2, and 3, respectively. Qualitative data suggested a favourable trial experience in groups 1 and 3.\ud \ud Discussion:\ud Group 2 retention rate was problematic and has implications for our next trial.\ud \ud Conclusion:\ud Our study suggests that a future trial to determine the effectiveness of BMEA treatment for women with CPP is feasible but with modifications to the study design

Analysis of design parameters in SIL-4 safety-critical computer

Nowadays, Safety-critical computers are extensively used in may civil domains like transportation including railways, avionics and automotive. We noticed that in design of some previous works, some critical safety design parameters like failure diagnostic coverage (DC) or common cause failure (CCF) ratio have not been seriously taken into account. Moreover, in some cases safety has not been compared with standard safety levels (IEC-61508 SIL1-SIL4) or even have not met them. Most often, it is not very clear that which part of the system is the Achilles' heel and how design can be improved to reach standard safety levels. Motivated by such design ambiguities, we aim to study the effect of various design parameters on safety in some prevalent safety configurations: 1oo2 and 2oo3. 1oo1 is also used as a reference. By employing Markov modeling, sensitivity of safety to each of the following critical design parameters is analyzed: failure rate of processing element, failure diagnostics coverage, common cause failures and repair rates. This study gives a deeper sense regarding influence of variation in design parameters over safety. Consequently, to meet appropriate safety integrity level, instead of improving some system parts blindly, it will be possible to make an informed decision on more relevant parameters. © 2017 IEEE

Design, modeling, expression, and chemoselective PEGylation of a new nanosize cysteine analog of erythropoietin

Reza Ahangari Cohan1, Armin Madadkar-Sobhani2,3, Hossein Khanahmad1, Farzin Roohvand4, Mohammad Reza Aghasadeghi4, Mohammad Hossein Hedayati5, Zahra Barghi5, Mehdi Shafiee Ardestani4, Davoud Nouri Inanlou1, Dariush Norouzian11Research and Development Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran; 2Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; 3Department of Life Sciences, Barcelona Supercomputing Center, Barcelona, Spain; 4Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, Iran; 5Quality Control Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, IranBackground: Recombinant human erythropoietin (rhEPO) is considered to be one of the most pivotal pharmaceutical drugs in the market because of its clinical application in the treatment of anemia-associated disorders worldwide. However, like other therapeutic proteins, it does not have suitable pharmacokinetic properties for it to be administrated at least two to three times per week. Chemoselective cysteine PEGylation, employing molecular dynamics and graphics in in silico studies, can be considered to overcome such a problem.Methods: A special kind of EPO analog was elicited based on a literature review, homology modeling, molecular dynamic simulation, and factors affecting the PEGylation reaction. Then, cDNA of the selected analog was generated by site-directed mutagenesis and subsequently cloned into the expression vector. The construct was transfected to Chinese hamster ovary/dhfr- cells, and highly expressed clones were selected via methotrexate amplification. Ion-immobilized affinity and size exclusion (SE) chromatography techniques were used to purify the expressed analog. Thereafter, chemoselective PEGylation was performed and a nanosize PEGylated EPO was obtained through dialysis. The in vitro biologic assay and in vivo pharmacokinetic parameters were studied. Finally, E31C analog Fourier transform infrared, analytical SE-high-performance liquid chromatography, zeta potential, and size before and after PEGylation were characterized.Results: The findings indicate that a novel nanosize EPO31-PEG has a five-fold longer terminal half-life in rats with similar biologic activity compared with unmodified rhEPO in proliferation cell assay. The results also show that EPO31-PEG size and charge versus unmodified protein was increased in a nanospectrum, and this may be one criterion of EPO biologic potency enhancement.Discussion: This kind of novel engineered nanosize PEGylated EPO has remarkable advantages over rhEPO.Keywords: nanoPEGylated EPO, cysteine PEGylation, pharmacokinetic propert

Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B) caused by Pathogenic Splice and Missense Variants of DYSF Gene among Iranians with Muscular Dystrophy.

BACKGROUND: The phenotypic range of limb-girdle muscular dystrophies (LGMDs) varies significantly because of genetic heterogeneity ranging from very mild to severe forms. Molecular analysis of the DYSF gene is challenging due to the wide range of mutations and associated complications in interpretations of novel DYSF variants with uncertain significance. Thus, in the current study, we performed the NGS analysis and its results are confirmed with Sanger sequencing to find the plausible disease-causing variants in patients with muscular dystrophy and their relatives via segregation analysis. MATERIALS AND METHODS: Nine patients with LGMD type 2B (LGMD2B) characteristics were screened for putative mutations by the whole-exome sequencing (WES) test. Either the patients themselves or their parents and first relatives were investigated in the segregation analysis through Sanger sequencing. The majority of variants were classified as pathogenic through American College of Medical Genetics and Genomics (ACMG) guidelines, segregation results, and in silico predictions. RESULTS: Results revealed eight variants in DYSF gene, including three splicing (c.1149+4A>G, c.2864+1G>A, and c.5785-7G>A), two nonsense (p.Gln112Ter and p.Trp2084Ter), two missense (p.Thr1546Pro and p.Tyr1032Cys), and one frameshift (p.Asp1067Ilefs), among nine Iranian families. One of the eight identified variants was novel, including p.Asp1067Ilefs, which was predicted to be likely pathogenic based on the ACMG guidelines. Notably, prediction tools suggested the damaging effects of studied variants on dysferlin structure. CONCLUSION: Conclusively, the current report introduced eight variants including a novel frameshift in DYSF gene with noticeable pathogenic effects. This study significantly can broaden the diagnostic spectrum of LGMD2B in combination with previous reports about DYSF mutations and may pave the way for a rapidly high-ranked identification of the accurate type of dysferlinopathy

Quercetin Impact in Pancreatic Cancer: An Overview on Its Therapeutic Effects

Pancreatic cancer (PC) is a lethal malignancy cancer, and its mortality rates have been increasing worldwide. Diagnosis of this cancer is complicated, as it does not often present symptoms, and most patients present an irremediable tumor having a 5-year survival rate after diagnosis. Regarding treatment, many concerns have also been raised, as most tumors are found at advanced stages. At present, anticancer compounds-rich foods have been utilized to control PC. Among such bioactive molecules, flavonoid compounds have shown excellent anticancer abilities, such as quercetin, which has been used as an adjunctive or alternative drug to PC treatment by inhibitory or stimulatory biological mechanisms including autophagy, apoptosis, cell growth reduction or inhibition, EMT, oxidative stress, and enhancing sensitivity to chemotherapy agents. The recognition that this natural product has beneficial effects on cancer treatment has boosted the researchers’ interest towards more extensive studies to use herbal medicine for anticancer purposes. In addition, due to the expensive cost and high rate of side effects of anticancer drugs, attempts have been made to use quercetin but also other flavonoids for preventing and treating PC. Based on related studies, it has been found that the quercetin compound has significant effect on cancerous cell lines as well as animal models. Therefore, it can be used as a supplementary drug to treat a variety of cancers, particularly pancreatic cancer. This review is aimed at discussing the therapeutic effects of quercetin by targeting the molecular signaling pathway and identifying antigrowth, cell proliferation, antioxidative stress, EMT, induction of apoptotic, and autophagic features.The authors acknowledge the Molecular Medicine Research Center, Bio-Medicine Institute, Tabriz University of Medical Sciences, and the Clinical Research Development Unit of Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran. This work was supported and funded by Tabriz University of Medical Sciences, Tabriz, Iran (grant number: 68344)

Expression of Cholera Toxin B–Proinsulin Fusion Protein in Lettuce and Tobacco Chloroplasts – Oral Administration Protects Against Development of Insulitis in Non-Obese Diabetic Mice

Lettuce and tobacco chloroplast transgenic lines expressing the cholera toxin B subunit–human proinsulin (CTB-Pins) fusion protein were generated. CTB-Pins accumulated up to ~16% of total soluble protein (TSP) in tobacco and up to ~2.5% of TSP in lettuce. Eight milligrams of powdered tobacco leaf material expressing CTB-Pins or, as negative controls, CTB–green fluorescent protein (CTB-GFP) or interferon–GFP (IFN-GFP), or untransformed leaf, were administered orally, each week for 7 weeks, to 5-week-old female non-obese diabetic (NOD) mice. The pancreas of CTB-Pins-treated mice showed decreased infiltration of cells characteristic of lymphocytes (insulitis); insulin-producing β-cells in the pancreatic islets of CTB-Pins-treated mice were significantly preserved, with lower blood or urine glucose levels, by contrast with the few β-cells remaining in the pancreatic islets of the negative controls. Increased expression of immunosuppressive cytokines, such as interleukin-4 and interleukin-10 (IL-4 and IL-10), was observed in the pancreas of CTB-Pins-treated NOD mice. Serum levels of immunoglobulin G1 (IgG1), but not IgG2a, were elevated in CTB-Pins-treated mice. Taken together, T-helper 2 (Th2) lymphocyte-mediated oral tolerance is a likely mechanism for the prevention of pancreatic insulitis and the preservation of insulin-producing β-cells. This is the first report of expression of a therapeutic protein in transgenic chloroplasts of an edible crop. Transplastomic lettuce plants expressing CTB-Pins grew normally and transgenes were maternally inherited in T1 progeny. This opens up the possibility for the low-cost production and delivery of human therapeutic proteins, and a strategy for the treatment of various other autoimmune diseases